Abstract P3-11-03: Novel Targeting of Semaphorin 7a-Mediated Survival Signaling in ER+ Breast Cancer
Authors: Rachel Steinmetz, Garhett Wyatt, Traci Lyons, Weston Porter, Lyndsey Crump
Journal: Cancer Research (2023)

Abstract Endocrine receptor-positive (ER+) breast cancers (BC) comprise over 70% of all breast cancers and are the leading cause of BC-related deaths in women. Despite available targeted therapies against ER+ BC, recurrence arises primarily due to the development of endocrine therapy resistance and metastases. Thus, there is an unmet need to identify novel biomarkers for treating ER+ BC patients with metastases. We have identified a neuroimmune molecule, Semaphorin 7a (SEMA7A), as a potential biomarker for endocrine therapy resistance, increased relapse and decreased overall survival in ER+ BC patients. We have also found that SEMA7A promotes tumor growth, angio- and lymphangiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis and endocrine therapy resistance in pre-clinical models. Specifically, we have shown that SEMA7A+ ER+ MCF7 tumors result in lung metastases that are resistant to the endocrine therapy, fulvestrant, in part, via downregulation of ER in vivo – posing the need to identify novel, druggable targets for SEMA7A+ ER+ BC. SEMA7A is a membrane-bound protein that we have shown can inhibit tumor cell death via integrin-mediated activation of PI3K/Akt pro-survival signaling. Thus, we hypothesized that that SEMA7A+ ER+ BC cells may be sensitive to PI3K inhibition in combination with fulvestrant. Our results demonstrate that SEMA7A+ MCF7 cells are sensitive to the combination of fulvestrant and PI3K inhibition by alpelisib, which is FDA approved for ER+ BC patients with activating mutations in PI3K; this combination also inhibited tumor cell growth and decreased tumor sphere formation. In complementary studies, we identified that Singleminded 2s (SIM2s), which is expressed in breast epithelial cells and inhibits EMT, is downregulated SEMA7A+ MCF7 tumors. Additionally, our studies show that while ER-mediated signaling turns on SEMA7A expression prolonged expression of SEMA7A results in downregulation of ER, and the loss of SIM2s causes downregulation of ER expression and upregulation of SEMA7A in MCF7 cells. Further, while SEMA7A-overexpressing (OE) tumor cells exhibit increased tumor-promoting PI3K/Akt survival signaling, we found that SIM2s plays a role in suppression of PI3K/Akt survival signaling. Therefore, we are investigating the interactions between SIM2s, SEMA7A and the survival signaling pathways involved in their crosstalk. Our recent results show that MCF7 SIM2-knockout (KO) cells exhibit increased SEMA7A promoter activity, SEMA7A expression, activation of Akt signaling, EMT phenotypes and decreased ER expression. Also, addition of exogenous SEMA7A protein reduces SIM2s expression and promoter activity. Since SIM2s correlates with inhibition of PI3K/Akt signaling and decreased SEMA7A, and SEMA7A promotes survival signaling, we are investigating additional therapeutic strategies to prevent endocrine therapy resistance via direct inhibition of SEMA7A and/or restoration of SIM2s, including inhibition of COX-2 and Akt signaling. Citation Format: Rachel Steinmetz, Garhett Wyatt, Traci Lyons, Weston Porter, Lyndsey Crump. Novel Targeting of Semaphorin 7a-Mediated Survival Signaling in ER+ Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-11-03.